Diabetic complications can be reduced by normalization of blood glucose levels via intensive insulin therapy. This treatment, while effective, bears the risk of an increased incidence of recurrent hypoglycemia. It blunts the central counterregulatory response to low blood glucose (counterregulatory failure) and thereby magnifies the risk of severe hypoglycemia and brain injury. This proposal is aimed at characterizing the CNS complications of intensive insulin therapy in type 1 diabetes; specifically, abnormalities in brain metabolism and its adaptations to recurrent hypoglycemia, the major cause of hypoglycemia unawareness. Previous data from our group from type 1 diabetic patients showed an increased ability of the brain to utilize alternate fuels under hypoglycemia, likely due to increased transporter protein expression. Preliminary in vivo NMR spectroscopy data from our animal model of recurrent hypoglycemia confirmed these findings since we found that infused monocarboxylic acids such as acetate and lactate could serve as energy substrates other than glucose and support brain metabolism under hypoglycemia. Antecedent recurrent hypoglycemia enhances these effects via a functional increase in alternate fuel transport into the brain. When testing lactate as an alternative fuel, we made the surprising observation that even though its uptake following exposure to recurrent hypoglycemia was enhanced, it still did not contribute significantly to overall brain oxidative capacity. Together this led us to hypothesize that recurrent hypoglycemia enhances uptake of monocarboxylic acids into the brain, which could be taken advantage of to support neuronal metabolism if a candidate fuel would not be subject to the same limitations as lactate. Because it does not depend on the potentially limiting step of pyruvate dehydrogenase conversion, beta-hydroxy-butyrate is one such fuel. Thus, we are proposing to determine the ability of the neuronal fuel beta-hydroxy-butyrate to support metabolic fluxes and to support human brain energy homeostasis under hypoglycemia. In a crossover study design, we will characterize brain ketone metabolism by carbon-13 NMR spectroscopy in healthy control and type 1 diabetic subjects during eu- and hypoglycemic clamp studies. By providing an alternate fuel when glucose is in limited supply, we will then be in the position to determine the contribution of ketones to overall brain metabolism. We will also characterize the ketone effect on neurotransmitter homeostasis. Our data will refine our understanding of brain monocarboxylic acid metabolism and will have important implications for creating new therapies to reduce brain dysfunction, injury and even death from hypoglycemia. Perhaps more importantly, this novel therapy may provide the opportunity to achieve tighter glucose control of type 1 diabetic patients, with reduced risk of brain injury from severe hypoglycemia, thus allowing more aggressive treatment and decreasing long term complications.